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. Author manuscript; available in PMC: 2021 Sep 1.
Published in final edited form as: Health Psychol. 2020 Sep;39(9):806–814. doi: 10.1037/hea0000862

Behavioral Strategies to Reduce Stress Reactivity in Opioid Use Disorder: Study Design

R Kathryn McHugh 1, Minh D Nguyen 1, Garrett M Fitzmaurice 1, Daniel G Dillon 1
PMCID: PMC8352497  NIHMSID: NIHMS1727563  PMID: 32833482

Abstract

Objectives:

More than 2 million people in the U.S. had an opioid use disorder in 2017. Treatment for opioid use disorder—particularly medication combined with psychosocial support—is effective for reducing opioid use and decreasing overdose risk. However, approximately 50% of people who receive treatment will relapse or dropout. Stress reactivity, defined as the subjective and physiological response to stress, is heightened in people with opioid use disorder and higher stress reactivity is associated with poorer outcomes. Preliminary studies suggest that stress reactivity may be a key mechanistic target for improving outcomes. This manuscript describes the design of an ongoing study examining behavioral strategies for reducing stress reactivity in adults with opioid use disorder. Our objective is to test the efficacy of two behavioral strategies for reducing stress reactivity and enhancing behavioral persistence in the context of stress (distress tolerance).

Methods.

We will recruit 120 adults with opioid use disorder and randomly assign them to brief training in (1) cognitive reappraisal, (2) affect labeling, or (3) a psychoeducational control. Participants will receive the training intervention followed by a laboratory stressor during which they will be instructed to apply the trained skill.

Results.

Subjective and physiological responses to stress will be measured as indices of stress reactivity and the stressor task will include a behavioral persistence component as a measure of distress tolerance.

Conclusions.

The ultimate goal of this study is to inform the development of behavioral interventions that can be used as an adjunct to medication-based treatment for opioid use disorder.

Keywords: opioid-related disorders, psychological stress, physiological stress, cognitive behavioral therapy

An estimated 2.1 million people in the U.S. meet diagnostic criteria for an opioid use disorder and more than 11 million people misuse opioids (Center for Behavioral Health Statistics and Quality, 2018). In 2017, more than 47,000 people died from opioid overdose, continuing the trend of increases in overdose fatalities since the late 1990s (Scholl, Seth, Kariisa, Wilson, & Baldwin, 2018). The devastating impact of the opioid epidemic on families and communities spurred its designation as a national public health emergency by the U.S. Department of Health and Human Services in October 2017.

The most effective available treatment for opioid use disorder consists of medication plus psychosocial supports (see (Committee on Medication-Assisted Treatment for Opioid Use Disorder, 2019). Despite the tremendous benefits of these treatments compared to alternatives (e.g., opioid detoxification only), however, approximately 50% of treated individuals either relapse or drop-out of treatment (Lee et al., 2018; Weiss et al., 2011). Accordingly, there is an urgent need to improve the efficacy of treatment for opioid use disorder.

In addition to their euphoric effects, opioids also relieve stress (Bershad, Miller, Norman, & de Wit, 2018) and therefore are highly negatively reinforcing. With chronic opioid use, central stress systems become sensitized (Xu, Van Bockstaele, Reyes, Bethea, & Valentino, 2004), contributing to sustained, heightened reactivity to stressors (Hyman, Fox, Hong, Doebrick, & Sinha, 2007) and providing enhanced motivation for behaviors that provide relief (Koob & Le Moal, 2008). Stress reactivity—the subjective and physiological response to stress—is a predictor of relapse (Sinha et al., 2011; Sinha, Garcia, Paliwal, Kreek, & Rounsaville, 2006) and treatment dropout (Panlilio et al., 2019) among people with substance use disorders.

Furthermore, alpha adrenergic medications that decrease stress reactivity have improved opioid outcomes in preliminary studies (Kowalczyk et al., 2015; Sinha, Kimmerling, Doebrick, & Kosten, 2007). Thus, stress reactivity is a promising target for improving outcomes in people with opioid use disorder.

Interpreting stressors as intolerable, harmful, or uncontrollable increases affective and physiological stress responses (e.g., Abela et al., 2011; Farris, Zvolensky, Otto, & Leyro, 2015). Cognitive-behavioral interventions that modify such interpretations are central to treatment for anxiety and depressive disorders (Barlow, Allen, & Choate, 2016), and have been applied to a wide array of disorders in which dysfunctional stress responses are implicated (Beck, 2008; Stappenbeck et al., 2015; Terry, Thompson, & Rhudy, 2015). Cognitive reappraisal is an effective and widely used strategy for modifying maladaptive interpretations of situations (Barlow et al., 2016; Lazarus & Alfert, 1964). Even brief training in cognitive reappraisal is effective for reducing harmful interpretations of stressors, and also reducing negative affective reactivity to stress (Burklund, Creswell, Irwin, & Lieberman, 2014; Terry et al., 2015; Webb, Miles, & Sheeran, 2012). Although cognitive reappraisal is a component of cognitive-behavioral interventions that have been tested in people with opioid use disorder, the specific role of cognitive reappraisal in these treatments—and its impact on stress reactivity—remains unclear.

Although cognitive reappraisal can reduce stress reactivity, its efficacy may be limited by the impact of stress on higher-order cognitive functioning (Hermans, Henckens, Joels, & Fernandez, 2014). In other words, it is difficult to use reappraisal when under high stress. This may be especially so for people with self-regulatory deficits and limited cognitive control (Gyurak, Goodkind, Kramer, Miller, & Levenson, 2012). Indeed, cognitive and self-regulatory deficits (e.g., limited working memory, faulty reasoning) are highly prevalent among people with opioid use disorder (Darke, McDonald, Kaye, & Torok, 2012; Rapeli et al., 2006), which may undercut the potentially beneficial effects of cognitive reappraisal. Accordingly, it would be helpful to consider approaches that also reduce stress reactivity but that require fewer cognitive resources. Simply labeling an affective state or stimulus (e.g., describing arousing negative feelings as “anger” or “fear”) can significantly reduce affective and physiological responses to stressful stimuli, relative to responses observed in control conditions (e.g., when labeling non-affective stimulus features; (Lieberman et al., 2007; Tabibnia, Lieberman, & Craske, 2008). In other words, affect labeling has similar effects to cognitive reappraisal (Burklund et al., 2014). Importantly, however, affect labeling reduces negative emotional states without requiring significant cognitive control. Affect labeling has been used to enhance the efficacy of cognitive-behavioral therapies for anxiety disorders (Niles, Craske, Lieberman, & Hur, 2015; Tabibnia et al., 2008) and it is a core feature of mindfulness-based treatments (see Creswell, Way, Eisenberger, & Lieberman, 2007). Investigating the efficacy of affect labeling in people with opioid use disorder would be worthwhile given evidence of diminished cognitive control in this population (Verdejo-Garcia & Perez-Garcia, 2007), which might make using reappraisal difficult.

This manuscript describes our trial testing the efficacy of cognitive reappraisal and affect labeling as brief interventions to reduce stress reactivity in people with opioid use disorder. The trial was informed by the Science of Behavioral Change program (SOBC; scienceofbehaviorchange.org), which applies an experimental medicine approach to behavior change. Specifically, SOBC focuses on identifying a mechanism that is linked to the target behavior, modifying that mechanism with an intervention, and testing whether the modification leads to the desired change in behavior.

In this study, we will use a clinical analogue design (see Clark, 2004) to isolate and test the effect of an acutely administered “dose” of behavioral strategies on stress reactivity in adults with opioid use disorder. Clinical trials of behavior therapy often test complex, multi-component interventions over several months. Although such trials provide a rigorous test of the efficacy of treatment for reducing symptoms, they lack precision for determining the specific mechanism of behavior change. By focusing on two tightly controlled interventions over a brief period of time, our design addresses this limitation and will allow for a more precise test of the efficacy of these interventions for reducing stress reactivity.

Consistent with the SOBC model of behavior change, we will examine the ability of cognitive reappraisal and affect labeling to (1) modify the hypothesized mechanism of change (stress reactivity) and (2) achieve behavior change (distress tolerance). In a secondary aim, we will examine whether baseline self-regulatory ability moderates the response to the interventions. Specifically, we aim to characterize whether people with greater self-regulatory deficits will have a smaller response to the cognitive reappraisal intervention (relative to affect labeling) due to the significant cognitive control associated with this approach (Buhle et al., 2014). Our model of behavior change for this project is presented in Figure 1.

Figure 1.

Figure 1.

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Project Conceptual Model of Behavior Change. Stress Reactivity is measured by the Positive and Negative Affectivity Scales (primary outcome) and peripheral physiological measures (secondary outcome). Distress tolerance is measured as time to discontinuation on the Computerized Mirror Tracing Persistence Task.

Method

This study is supported by the National Institutes of Health (NIH) Science of Behavior Change Common Fund Program through an award administered by the National Institute on Drug Abuse (R21 DA046937). The NIH was not involved in the design of this study or the decision to publish this manuscript. The study was approved by the Partners Healthcare Institutional Review Board. The latest approved protocol at the time of this writing is Version 2.3 (version date 11/27/2019). We do not anticipate any significant protocol modifications; yet, if the need for such a modification arises (e.g., new information about procedures or human subjects protections becomes available), this will be communicated to the Institutional Review Board, the study sponsor, and study registries (clinicaltrials.gov, see below).

Design Overview

Our first aim is to test the effects of cognitive reappraisal and affect labeling on subjective and physiological responses to a laboratory stressor. Relative to a psychoeducational control intervention, both cognitive reappraisal and affect labeling are expected to reduce stress reactivity. The second aim is to test the effect of these strategies on a short-term behavioral outcome: behavioral persistence during a stressful task. We hypothesize that the active interventions will enhance persistence compared to the psychoeducational control. Finally, in an exploratory aim we will investigate whether deficits in self-regulation moderate responses to the interventions.

An overview of our study design is presented in Figure 2. Following the initial eligibility screening, participants will complete the informed consent process. Either the PI or a designee of the PI (e.g., trained research assistant), will obtain informed consent. Those who provide informed consent will undergo further eligibility screening including a breath alcohol test and an assessment of opioid withdrawal (Clinical Opiate Withdrawal Scale; COWS) (Wesson & Ling, 2003). Participants who are currently experiencing withdrawal will be re-assessed at a later time. Eligible participants will then complete a battery of self-report and interviewer-administered measures, described in the Measures section below, and will be randomly assigned to one of three interventions. Each participant will then complete baseline physiological measures (skin conductance and salivary cortisol), followed by one of the interventions, and we will then administer the stressor task. Measures of physiological stress will be collected during stress exposure and self-report of negative affect will be repeated immediately following the stressor.

Figure 2.

Figure 2.

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Study Design Overview

Participant Selection and Recruitment

We plan to enroll 120 adults age 18 years and older diagnosed with opioid use disorder. Exclusion criteria include: current opioid withdrawal (based on COWS assessment), presence of another substance use disorder requiring immediate treatment (e.g., alcohol detoxification), endocrine disease or current steroid prescription, major acute psychiatric (e.g., acute mania or psychosis) or medical condition (e.g., acute pain condition that would limit the ability to manipulate a mouse for the computer task) that would interfere with the ability to complete study procedures, and signs of acute intoxication or positive breath alcohol test.

Participants will be recruited primarily from the substance use disorder treatment program of an academically affiliated psychiatric hospital. This program provides a continuum of substance use disorder care, including inpatient, residential, partial hospitalization and outpatient services. The treatment consists of medication management, group and individual behavioral/psychosocial treatment, family therapy and case management services. Participants will be recruited via either self-selection or invitation to participate by a member of the study staff.

Procedures

Allocation and masking.

Randomization was determined using a random number generator (https://www.randomizer.org) by a member of the study staff who is not involved in recruitment, enrollment or data analysis. In this behavioral intervention study, the experimenter cannot be blind to the condition; however, the randomized condition is provided to the experimenter in a sealed envelope, which cannot be opened until after enrollment and determination of eligibility to minimize bias in subject selection. Furthermore, the participant cannot be blinded to the condition in this trial; however, the study hypotheses are not disclosed to participants. The experimenter remains blind to study condition until following the administration of the COWS and Digit Span (i.e., the interviewer-assessed measures). The PI and study biostatistician will both remain blind to study condition until the completion of data analysis. In this low-risk study testing of brief behavioral interventions, we do not anticipate a reason for unblinding. Spontaneously reported adverse events or other unanticipated problems will be reported to the IRB in accordance with local policies for adverse event monitoring and reporting.

Interventions.

The three interventions were developed by the study investigators and informed by the literature on behavioral stress modification. The interventions were pilot tested to ensure a similar duration (approximately 5–6 minutes). Prior research has found that participants can be effectively trained in skills such as cognitive reappraisal in similar brief, experimental designs (Webb et al., 2012). All interventions were standardized using scripts, which will be read to participants by a member of the study staff. The study interventions include: Affect Labeling and Cognitive Reappraisal (active conditions) and a Psychoeducation comparison (control condition). Participants in the active conditions will be instructed to practice the skill during the stress induction; participants in the control condition will not receive instructions for what to do during the stress induction. Participants will be informed that the task is stressful during the informed consent process and prior to engaging in the task.

In the Affect Labeling condition, the experimenter will provide a definition of affect labeling and a description of how to engage in this skill. The instructions for this task focus specifically on affect labeling and do not include related components seen in mindfulness-based interventions, such as non-judgmental awareness and modifying responses to affective states (Bowen et al., 2014). The experimenter will then read two vignettes of stressful situations (a social stressor and being late for a job interview). During each vignette, participants will be instructed to imagine themselves in this situation; after each vignette the participant will be asked to practice affect labeling. For example, the job interview vignette consists of a description of being stuck in traffic and late for a job interview. Participants will be asked to notice any negative emotions that they might be feeling and to label those emotions (e.g., frustrated, anxious, guilty). The experimenter will provide corrective feedback as needed and another opportunity to practice if the skill is not correctly implemented. Participants will then be instructed that they should use this strategy during the stressor task. Participants will receive reminders before the task begins and during standardized breaks in the stressor and will be asked to engage in affect labeling aloud so that the experimenter can monitor compliance.

The Cognitive Reappraisal condition consists of a definition of cognitive reappraisal, followed by instructions for re-appraising emotions and the two vignettes. This was developed based on a review of both the experimental and clinical literature on cognitive reappraisal. Participants will be instructed that they can either think about a situation from a different perspective or focus on the ability to cope with the emotions. For example, following the job interview vignette participants will be asked to envision how they could change their thinking in that situation by regarding it from another perspective (e.g., “Everyone has been stuck in traffic, the interviewer will probably understand”) or by describing their ability to cope (e.g., “This is really frustrating, but I can listen to music to calm down”). Following practice with each vignette, participants will be reminded to reappraise their cognitions aloud during the stressor task. Compliance will be monitored by the experimenter.

The Psychoeducational Comparison condition consists of a definition of the stress response and its importance for adaptive responding to stressors. The intervention does not include any information about strategies to modify stress, yet informs participants that knowing more about stress can help people cope. As in the active conditions, the two vignettes are read to participants. However, in this condition the participants are only instructed to imagine themselves in each situation—they are not given any instructions regarding how to modify their experience.

Stressor task.

Following the completion of the interventions, participants will complete the stress induction. The Computerized Mirror Tracing Persistence Task (MTPT; Strong et al., 2003) is a standardized computer-based task that entails tracing a shape on a computer screen using a mouse. The task is challenging because the movement of the cursor on the screen is opposite to the movement of the mouse. When an error is made, or if the participant pauses, the cursor returns to the beginning and a loud, aversive tone is played. Based on pilot trials, the tone is set at a standardized volume to ensure that it is irritating without being painful (80% of maximum). The task consists of three trials of increasing difficulty, each lasting two minutes. A final trial serves to measure distress tolerance. During this trial, participants will be told that they can stop at any time, but they are incentivized to perform as well as possible. Participants will be informed that they can earn an additional $5 if they are among the top performers on the task; modest incentives (e.g., <$10, opportunity to be entered into a raffle for $40) have been successfully used in prior studies (McHugh et al., 2016; Schloss & Haaga, 2011). All participants will receive this additional compensation regardless of performance; this deception will be disclosed during a session debriefing with the experimenter. This task has been used in prior studies of opioid misuse and opioid use disorder and it consistently elicits a robust stress response (e.g., McHugh & Otto, 2011; McHugh et al., 2016).

Because there are many available methods for inducing stress, which can be broadly categorized as individualized or standardized, here we provide our rationale for selecting the MTPT. Individualized stressors, such as script-driven imagery (Sinha, Fuse, Aubin, & O’Malley, 2000), are presumably salient to participants and thus may maximize perceived stress. However, limitations of individualized stressors are the lack of standardization across participants and the increase in participant burden. By contrast, standardized stressors ensure that the exposure is consistent across participants, yet they might not be salient to a given individual, thus precluding a robust stress response. We selected a standardized stressor—the MTPT—for this study because we wanted to ensure consistency across participants while avoiding potential confounds associated with individualized stressors, such as variability in stressor severity. The possibility that some participants may exhibit a blunted response to the stressor is a limitation; nonetheless, the MTPT has been shown to elicit a robust stress response in prior studies with this population (McHugh & Otto, 2012).

Measures and Outcomes

Study measures will include self-report, behavioral, and physiological assessments. The primary study outcomes include: self-reported stress reactivity (Aim 1) and behavioral distress tolerance (Aim 2). Secondary aims include physiological measures of stress reactivity, including salivary cortisol and skin conductance levels.

Self-reported stress reactivity will consist of changes in both negative affect and opioid craving from pre- to post-stressor. Negative affect will be measured using the Negative Affect subscale of the Positive and Negative Affect Schedule (PANAS; Watson, Clark, & Tellegen, 1988). The PANAS is a widely validated measure that examines the extent to which the respondent is experiencing specific emotions in the moment (e.g., scared, irritable). We will measure opioid craving with the Opioid Craving Scale (OCS; McHugh et al., 2014). The OCS is a validated measure of opioid craving that is a modification of the Cocaine Craving Scale (Weiss et al., 2003). Scores on this measure are associated with risk for opioid relapse (McHugh et al., 2014).

Physiological measures include salivary cortisol and skin conductance level; these will be secondary outcomes in Aim 2. These physiological measures were chosen based on prior studies of stress reactivity in people with substance use disorders, to measure hypothalamic-pituitary-adrenal (HPA) axis response (cortisol) and sympathetic nervous system activation (skin conductance) (e.g., Brewer et al., 2009; Fatseas et al., 2011). To control for the diurnal variation in cortisol, study procedures will be conducted between 12PM-5PM. Following informed consent and completion of a battery of self-report and experimenter-administered assessments, participants will undergo a baseline period including physiological data collection. This will allow participants to acclimate to the environment before the baseline physiological data are collected. During the 6-minute baseline period, participants will be instructed to sit quietly while skin conductance levels are collected. Following this baseline, the first saliva sample for cortisol will be collected. During the stressor task, skin conductance will continue to be collected. Saliva samples for cortisol will be immediately collected after the completion of the stress task and again 20 minutes after the completion of the task (consistent with the peak salivary cortisol response to stress; Dickerson & Kemeny, 2004). Saliva will be collected using the passive drool method collected through a SalivaBio tube with the assistance of a saliva collection aid (Salimetrics, LLC, State College, PA). Salivary cortisol is highly correlated with serum cortisol (Hellhammer, Wust, & Kudielka, 2009), and can be collected non-invasively. Skin conductance data will be collected using the eSense SC system (Mindfield Biosystems, Inc., Berlin, Germany) on a tablet computer (Hinrichs et al., 2017).

Self-regulation (hypothesized moderator) will be measured using a self-report measure of delay discounting, or the tendency to overvalue immediate relative to delayed rewards (Monetary Choice Questionnaire; (Kirby & Marakovic, 1996), and a cognitive measure of working memory, the Digit Span Task (Wechsler, 1997). These two tasks will be used to capture two distinct elements of self-regulation (decision-making and working memory), and both will be tested in our exploratory secondary analysis. These were selected for several reasons: (1) they are both malleable with treatment (Bickel, Yi, Landes, Hill, & Baxter, 2011; Rass et al., 2015), (2) they are related to treatment outcomes in people with substance use disorders (see Stevens et al., 2014), and (3) they allow us to consider the relevance of both global (working memory) and specific (overvaluation of immediate rewards) domains of self-regulation. Delay discounting rates will be estimated according to standardized scoring procedures to obtain a k value, representing the degree to which respondents discount delayed rewards. As these two tasks capture distinct elements of self-regulation, they will be considered separately in our secondary analyses.

Data Analysis Plan

Descriptive statistics will be calculated to assess for outliers or skewed variables. Data will be transformed if needed. Inferential statistics will be calculated for three aims. The first aim will test the hypothesis that the active interventions will be associated with lower stress reactivity than the control condition. This will involve computing analyses of covariance (ANCOVA) with baseline stress markers as covariates and study group as the independent variable, with post-stressor stress markers as the dependent variables. The second aim will test the hypothesis that the active interventions will be associated with greater behavioral tolerance of a stressor. This will be tested using an ANOVA with study group as the independent variable and distress tolerance (i.e., time to discontinuation of the task) as the dependent variable. Analyses for both aims will include contrasts for the comparison between each active intervention (affect labeling and cognitive reappraisal) and the control condition. Finally, in our secondary aim, we will test whether baseline differences in self-regulation moderate the response to the active interventions, by testing the interaction effects of self-regulation and study group in the ANCOVA and ANOVA models described above (reflecting moderation of the effect of group on stress reactivity and distress tolerance, respectively). The effect of interest in both of these models is the interaction between self-regulation and study group.

In an exploratory analysis, we will test whether stress reactivity mediates the association between the intervention (group) and distress tolerance (behavioral outcome). Specifically, the potential mediating effect will be assessed in linear regression models for distress tolerance (behavioral outcome) that include indicator variables for study group in addition to post-baseline changes in stress reactivity markers. Under strong assumptions of no unmeasured confounding, the difference between study group regression coefficients in models with and without adjustment for post-baseline changes in stress reactivity markers can be interpreted as the mediated or indirect effect.

Furthermore, we will investigate main and interaction effects of sex in all analyses. Data suggest that women with opioid use disorder report more coping motives for use (McHugh et al., 2013), are more commonly diagnosed with stress-related disorders such as depression and posttraumatic stress disorder (McHugh et al., 2013), and report greater increases in opioid craving following stress relative to men (Moran et al., 2018). Accordingly, we plan to control for sex in all analyses and we will conduct exploratory tests of any moderational effects of sex.

The sample size for this study was determined based on a power analysis, which estimated the minimum effect size detectable at 80% power and a significance level of .05. Similar prior studies that examined brief, acute doses of interventions (e.g., cognitive reappraisal) have demonstrated effects sizes in the small to medium range (Webb et al., 2012). We elected to statistically power our study to detect a medium effect size or larger, which we believed would be the minimum clinically meaningful difference. A sample of 120 participants (40 per group) had power of at least 80% to detect an effect size of d = 0.58 (a medium effect size) for Aims 1 and 2.

Procedures to Enhance Rigor, Reproducibility and Transparency

We will use several procedures to facilitate transparency, rigor, and reproducibility. Data for this study will be collected using a HIPAA-compliant electronic data capture system, REDCap (Harris et al., 2009). REDCap provides features to ensure data integrity, such as audit trails and real-time validation. Data management is also closely monitored by the study Principal Investigator (PI) to ensure the quality and integrity of the data. Biological specimens (saliva) are frozen after collection and stored in a locked freezer in a locked laboratory. These specimens will then be transported by research staff to an external lab for the quantification of cortisol. To ensure data integrity, we will monitor and record chain of possession of the biospecimens. Additionally, all study staff receive training in the responsible conduct of research and the importance of ensuring data validity; ongoing training on these topics occurs on a monthly basis with lab staff. The LabArchives electronic lab notebook platform will be being used to provide further monitoring of data integrity. We chose to use an electronic lab notebook because it allows for a single, central repository for all study staff to access the most up-to-date protocol and procedural manuals, to track the implementation of quality control procedures (e.g., regular data audits), and to report all steps of data processing and analysis. All entries are time and date stamped and are linked to the author to allow for PI oversight.

In support of transparency and public accessibility of the study aims, design and findings, this study is registered at clinicaltrials.gov (NCT03616379). As an NIH-funded clinical trial, registry at clinicaltrials.gov is required. At this site, information on study aims, eligibility criteria, measures and planned analyses are provided. Consistent with NIH guidelines, results will be made available on clinicaltrials.gov within one year of study completion. Furthermore, any publications directly resulting from this project will be made freely available to the public in PubMed Central (https://publicaccess.nih.gov/). Our study dataset will contain sensitive data about a vulnerable population (people with opioid use disorder). Any data sharing will be done in accordance with all applicable local and federal regulations, including necessary procedures for adequate de-identification of study data. The study PI also maintains a page on the Open Science Framework website (https://osf.io/8ns7y/); this is not specific to the current study, but rather is used to enhance reproducibility and transparency of studies conducted in her laboratory. The goal of this page is to complement the clinicaltrials.gov record and not to be a redundant resource.

Discussion

Although currently available treatments for opioid use disorder are frequently effective and life-saving (Committee on Medication-Assisted Treatment for Opioid Use Disorder, 2019), there is significant room for improvement. In our trial, we will test two behavioral interventions that have promise for reducing stress reactivity, a vulnerability factor for relapse in opioid use disorder. Our study will investigate the ability of these interventions to reduce subjective and physiological responses to stress and to increase persistence in the context of stress.

The study has implications for understanding stress reactivity and treatment of opioid use disorder. We expect the study to clarify the relative efficacy of two interventions for the reduction of stress reactivity—namely, cognitive reappraisal and affect labeling. We will also determine whether reduced stress reactivity elicits a short-term change in behavior—namely, increased persistence. Behavioral persistence is important because the ability to persist toward a goal, without seeking immediate stress relief, is essential for recovery from substance use disorders. Although our focus is opioid use disorder, a greater understanding of strategies for reducing stress reactivity should be applicable to the wide array of conditions in which exaggerated stress responses drive maladaptive behavior.

Our study also has some limitations. Although the use of a clinical analogue design permits greater control over the effect of the intervention on the target mechanism, it is likely that these interventions would lead to stronger effects in a multi-session trial. Specifically, providing more time for participants to acquire and practice the skills required for effective reappraisal or affect labeling would likely lead to greater stress reduction. Nonetheless, the literature reports robust responses for single-trials of these interventions (Burklund et al., 2014), which support our use of a single-session trial. Another limitation is that we are not excluding participants with co-occurring psychiatric disorders or other substance use disorders. This heterogeneity can introduce challenges to internal validity, but excluding these disorders would present a significant challenge to generalizability and feasibility because polysubstance use and co-occurring psychiatric disorders are highly prevalent among people with opioid use disorder (Conway, Compton, Stinson, & Grant, 2006; McCabe, West, Jutkiewicz, & Boyd, 2017).

Importantly, the current study design does not itself serve as a test of cognitive-behavioral approaches, which are administered over multiple sessions and focus on skill rehearsal and acquisition over time. The goal of our study is to precisely test the success of acute administration of specific intervention components on their target mechanism (stress reactivity). The results of this study will potentially inform future directions in two domains: (1) optimizing cognitive-behavioral and/or mindfulness-based interventions for reducing stress reactivity in opioid use disorder, and (2) developing personalized interventions (e.g., selecting interventions requiring few cognitive resources for people with self-regulatory deficits). If our working hypotheses are supported, the next step will be to conduct a clinical trial testing these cognitive-behavioral strategies within a broader treatment package designed to optimize their acquisition and foster sustained benefits.

Acknowledgments

This research was supported in part by a grant from the National Institute on Drug Abuse (R21 DA046937).

Footnotes

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03616379

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